In this proposal I build on some very exciting preliminary data regarding a role for the vitamin D receptor (VDR) in Gardner's syndrome, a derivative of familial adenomatous polyposis (FAP). FAP is an autosomal dominant disease caused by a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene and is characterized by gastrointestinal polyps. In some FAP patients, those with Gardner's syndrome, extra-colonic lesions including osteomas, bone opacity, desmoids and large epidermoid cysts occur. These extracolonic manifestations make Gardner's syndrome particularly difficult to manage clinically. Curiously, none of the APC mutant animal models develop these extra-colonic manifestations of FAP indicating that other, modifying genetic, epigenetic or environmental factors work on the FAP background to result in Gardner's Syndrome in the human. Remarkably, when we crossed VDR-/- animals with APC1638N/+ mutant animals we observed the rapid development of large epidermoid cysts that were not present in either of the parental strains. These cysts were histologically indistinguishable from those that occur in patients with Gardner's syndrome. Given that defects in bone also occur in these patients, as well as the strong association of the VDR with skin lesions, we hypothesize that the VDR-/-:APC1638N/+ mouse may represent a model of Gardner's syndrome. In this proposal, I propose experiments designed to directly examine: 1. if the other extra-colonic lesions characteristic of Gardner's syndrome also occur in these animals, 2. how the VDR attenuates Gardner's syndrome, and 3.if the polymorphisms of Vitamin D Gene Pathway are related to the extra-colonic lesions as well as colorectal cancer in FAP patient. PUBLIC HEALTH RELEVANCE: Gardner's syndrome is a variant of FAP, which has a variety of extra-colonic manifestations such as fibroma, osteoma, and most characteristically large epidermoid cysts. Epidermal cysts are the most common skin lesions of Gardner's syndrome, typically occurring at an earlier age and at multiple sites, including the face, scalp, and extremities. Due to the poor quality of life and the rapid development of polyps to colorectal cancer, Gardner's syndrome is actually considered a severe life threatening disease. Consequently, early identification and therapy of the disease are critical through the development of appropriate model organisms. Bone defects and multiple skin lesions characterize Gardner's syndrome and our preliminary data provides evidence that alterations in vitamin D receptor expression or function coupled with APC mutation may play a role this deadly disease.